Raltegravir received accelerated approval from the U.S. Food and Drug Administration (FDA) in October 2007 and traditional approval in 2009 for use by adults with HIV strains that are resistant to multiple antiretroviral agents and by those who have ongoing viral replication while receiving antiretroviral therapy. In July 2009, raltegravir was approved for use in initial therapy in adults. In 2012, it was approved for use in children 2 years of age and older, and in 2013, it was approved for use in children aged 4 weeks and older. It is intended for use as part of combination therapy. Raltegravir was the first agent in the class of integrase inhibitors to be approved by the FDA. It inhibits integration of reverse-transcribed HIV DNA into the chromosomes of host cells.

FDA approval was based on 24-week results from 2 randomized, placebo-controlled Phase III studies in patients with resistance to at least 1 agent in each of the protease inhibitor, nucleoside analogue, and nonnucleoside reverse transcriptase inhibitor classes. Patients received either raltegravir or placebo, plus a background regimen selected on the basis of resistance profiles. At 24 weeks, the raltegravir groups had greater decreases in HIV RNA and higher rates of viral suppression to <400 copies/mL and to <50 copies/mL than did the comparator group; these differences were statistically significant.(1)

Formulation and Dosing

Raltegravir is available in film-coated tablets, and in both chewable tablets and a powder formulation for oral suspension for pediatric administration. Recommended dosing is twice daily.

Dosing of Raltegravir

Adult

400 mg BID

Pediatric

Age <4 weeks

Not FDA approved

Age ≥4 weeks (and weight ≥3 kg)

Weight:

3 to <4 kg

Oral suspension 20 mg (1 mL) BID

4 to <6 kg

Oral suspension 30 mg (1.5 mL) BID

6 to <8 kg

Oral suspension 40 mg (2 mL) BID

8 to <11 kg

Oral suspension 60 mg (3 mL) BID

11 to <14 kg

Oral suspension 80 mg (4 mL) BID or chewable tablet 75 mg BID

14 to <20 kg

Oral suspension 100 mg (5 mL) BID or chewable tablet 100 mg BID

20 to <25 kg

Chewable tablet 150 mg BID

25 to <28 kg

Film-coated tablet 400 mg BID or chewable tablet 150 mg BID

28 to <40 kg

Film-coated tablet 400 mg BID or chewable tablet 200 mg BID

≥40 kg

Film-coated tablet 400 mg BID or chewable tablet 300 mg BID

Abbreviations: BID = twice daily

Note: The oral suspension is approved for pediatric patients weighing <20 kg; the chewable tablet is approved for pediatric patients weighing ≥11 kg. These formulations and the film-coated tablet formulation are not bioequivalent; follow specific dosing instructions for each formulation. The maximum dosage of oral suspension is 100 mg BID; the maximum dosage of chewable tablets is 300 mg BID.

Raltegravir must be used in combination with other antiretroviral medications.

Use in Initial vs Subsequent Therapy

Current adult and adolescent treatment guidelines of the U.S. Department of Health and Human Services state that the combination of raltegravir plus tenofovir/emtricitabine is a "preferred" regimen for initial treatment of HIV infection, and raltegravir plus abacavir/lamivudine is an "alternative" regimen.

In initial therapy, a randomized double-blind noninferiority comparison of raltegravir and efavirenz, each in combination with tenofovir + emtricitabine, found similar rates of virologic suppression to <50 copies/mL at 48 weeks: 86% in the raltegravir arm and 82% in the efavirenz group.(2) CD4 increases also were similar in the two groups: 189 cells/µL and 163 cells/µL, respectively.

In treatment-naive individuals, raltegravir was compared with darunavir + ritonavir and with atazanavir + ritonavir; each was given in combination with tenofovir/emtricitabine. At week 96 (the primary endpoint), by intention to treat (snapshot) analysis, the rate of virologic suppression to <50 copies/mL was 80% in the raltegravir group, 73% in the darunavir + ritonavir group, and 63% in the atazanavir + ritonavir group; the difference with each comparator was statistically significant. The differences in efficacy were driven primarily by higher rates of adverse effects in the comparator groups. Mean increases in CD4 cell counts were similar in all treatment groups.(3)

Also in initial therapy, a randomized double-blind study compared raltegravir and dolutegravir, each given in combination with investigator-selected nucleoside analogues, either tenofovir + emtricitabine or abacavir + lamivudine. At 48 weeks, by snapshot analysis, 85% of the raltegravir group and 88% of the dolutegravir group achieved HIV RNA suppression to <50 copies/mL; this difference was not statistically significant. In subjects with HIV RNA >100,000 copies/mL at baseline, HIV RNA suppression rates were 75% and 82%, respectively. The median CD4 increase was 230 cells/µL in each group.(4)

In treatment-experienced patients with resistance to at least 2 classes of antiretrovirals but no previous exposure to integrase inhibitors, a randomized controlled study compared raltegravir and dolutegravir (50 mg once daily) each in combination with other antiretrovirals as selected by investigators (background regimens were required to include at least 1 agent with full activity against HIV). At 48 weeks, higher rates of virologic failure were seen in the raltegravir group: 64% of patients in the raltegravir group and 71% of patients in the dolutegravir group had HIV RNA levels of <50 copies/mL (p = .03). Mean CD4 count increases were 153 and 162 cells/µL cells/µL, respectively.(5)

In treatment-experienced patients with resistance to 3 classes of antiretrovirals (nucleoside analogues, nonnucleoside reverse transcriptase inhibitors, and protease inhibitors) and ongoing viral replication, 2 Phase III studies (described above in "Approval") compared raltegravir with placebo, each given in combination with an optimized background regimen. In combined analysis, the groups that received raltegravir had higher rates of virologic suppression at 24 and 48 weeks than the groups that received placebo (at 48 weeks, HIV RNA was <400 copies/mL in 73% of raltegravir recipients vs 37% of placebo recipients, and <50 copies/mL in 62% vs 33%, respectively).(1) These differences were statistically significant (p < .001). Virologic suppression was closely correlated with having at least 1 active agent in the background antiretroviral regimen, and the inclusion of enfuvirtide or darunavir in the regimen of those without previous exposure to these drugs substantially improved the rates of virologic response. In the raltegravir treatment groups, the mean increase in CD4 count was higher than in the placebo group (109 cells/µL vs 45 cells/µL at 48 weeks; p < .001).(1,6)

A smaller Phase II randomized controlled trial, also involving patients with advanced HIV disease, extensive treatment experience, and resistance to at least 1 agent in each of 3 classes, compared 3 dosages of raltegravir (200 mg, 400 mg, and 600 mg, administered twice daily) with placebo. All participants were also given an optimized background regimen (tipranavir and darunavir were not available for use). At 24 weeks, by intention-to-treat analysis, the proportion of patients with HIV RNA levels of <50 copies/mL was 56-67% in the raltegravir groups and 13% in the placebo group (p < .0001 for comparison of each raltegravir dose with placebo). All participants were continued on open-label raltegravir (at the 400 mg twice daily dosage) to 48 weeks; at this time point, the proportion with HIV RNA levels of <50 copies/mL was 46-64%. As in the Phase III studies, the presence of other active antiretroviral agents (including enfuvirtide) in the background regimen substantially increased the rates of virologic suppression. The raltegravir groups had greater increases in CD4 cell counts at 24 weeks (60-102 cells/µL) than the placebo group (8 cells/µL).(7,8)

Potential Adverse Effects

Symptomatic adverse effects of raltegravir are uncommon but include nausea, headache, fatigue, and muscle aches. Rash and hypersensitivity reactions have been reported. Laboratory abnormalities include increases in pancreatic amylase and hepatic transaminase levels.(6,7,9) In one study, raltegravir caused less adverse impact on lipid levels and on bone mineral density than did atazanavir + ritonavir or darunavir + ritonavir.(3)

It is important to assess patient motivation and discuss possible adverse effects and strategies for their management before treatment with raltegravir is initiated.

Raltegravir interacts with several medications, including other antiretroviral agents. Raltegravir does not interact with the hepatic cytochrome P450 enzyme system. It is metabolized primarily by glucuronidation, particularly by uridine diphosphate glucuronosyltransferase (UGT) 1A1. Inducers or inhibitors of UGT 1A1 may affect serum levels of raltegravir. For example, rifampin induces raltegravir glucuronidation and substantially decreases raltegravir concentrations; the dosage of raltegravir must be increased if given concomitantly with rifampin. The nonnucleoside analogues efavirenz and etravirine and the protease inhibitor combination of tipranavir + ritonavir also lower raltegravir concentrations by this mechanism; however, the therapeutic significance of these interactions has not been defined. Other strong UGT 1A1 inducers such as phenobarbital and phenytoin have not been studied in combination with raltegravir.(6,10)

Inhibitors of UGT 1A1, including atazanavir, may increase raltegravir levels; the interaction with atazanavir does not appear to be clinically significant.(6)

Divalent cations (such as magnesium, calcium, and iron) may bind integrase inhibitors and interfere with their absorption and activity. Administration of an antacid containing aluminum and/or magnesium hydroxide with raltegravir or within 2 hours before or after raltegravir can reduce plasma raltegravir levels by 50%; these agents should not be taken within 2 hours of raltegravir. Simultaneous administration of calcium carbonate antacid with raltegravir results in 30% reduction in raltegravir trough levels, but dosage adjustment is not currently recommended. Proton pump inhibitors and H2 receptor antagonists do not affect raltegravir concentrations.(6)

Information on drug interactions should be consulted, as dosage adjustments are frequently required and some combinations are contraindicated.

Resistance

Resistance to raltegravir is associated with the selection of 1 or more of several resistance mutations; however, the resistance profile of raltegravir in human subjects has not been characterized fully. In vitro and in vivo studies of raltegravir show the emergence of a number of integrase mutations. In the clinical data currently available, three main genetic pathways to resistance have been identified. These involve Y143C/H/R plus additional mutations (L74M, T97A, G163R, S230R), Q148H/K/R plus additional mutations (E138K, G140A/S), or N155H plus additional mutations (L74M, T92Q, T97A, V151I, G163R). Increasing numbers of these mutations, as well as specific combinations, appear to be associated with greater degrees of reduced susceptibility to raltegravir and to other integrase inhibitors.(9,11)

In studies of initial therapy, emergent resistance to raltegravir also usually involved development of the reverse transcriptase mutations M184I or M184V (which confer resistance to lamivudine and emtricitabine), with or without mutations related to other components of the antiretroviral regimen.

Implications of raltegravir resistance for treatment with other antiretrovirals

Resistance mutations selected by raltegravir may confer resistance to other integrase inhibitors. Raltegravir-resistant HIV strains generally exhibit cross-resistance to elvitegravir.(12,13,14) The efficacy of dolutegravir may be sharply reduced by certain mutations, notably by Q148H/R in conjunction with 1 or more other integrase inhibitor mutations.(15,16)

Raltegravir mutations are not expected to affect sensitivity to other classes of antiretroviral agents.

Implications of resistance to other antiretrovirals for raltegravir treatment

Resistance mutations selected by other integrase inhibitors may contribute to raltegravir resistance; cross-resistance with elvitegravir is common, and cross-resistance with dolutegravir is likely.(13,14) Additional data from studies of integrase inhibitors will be needed to define resistance in this class of medications.

Resistance mutations selected by other classes of antiretrovirals are not expected to contribute to raltegravir resistance.